1,4-(diphenlyalkyl) piperazine derivatives

ABSTRACT

This invention relates to novel compounds of the formula  I!, ##STR1## wherein R 1  and R 2  are the same or different and each represents a lower alkoxy group; A and B are the same or different and each represents a lower alkylene group. 
     The compounds of this invention have affinities for sigma receptors and are useful for therapeutic agents for cerebral neural function disorders such as dementia, depression, schizophrenia and anxiety neurosis, diseases accompanying abnormal immune response and cryptorrhea, digestive ulcer, etc.

TECHNICAL FIELD

The present invention relates to novel 1,4-(diphenylalkyl)piperazinederivatives which have affinities for sigma receptors and are useful fortherapeutic agents for cerebral neural function disorders such asdementia, depression, schizophrenia and anxiety neurosis, diseasesaccompanying abnormal immune response and cryptorrhea, digestive ulcer,etc.

BACKGROUND ART

Many studies on sigma receptors have recently been made, and it has beenfound out that compounds having high affinities for the sigma receptorare useful for therapeutic agents for cerebral neural function disorderssuch as dementia, depression, schizophrenia and anxiety neurosis,diseases accompanying abnormal immune response and cryptorrhea,digestive ulcer, etc. (Journal of Neuropsychiatry, 1, 7-15 (1989); Eur.J. Biochem., 200, 633-642 (1991); J. Pharmacol. Exp. Ther., 255,1354-1359 (1990)).

On the other hand, 1,4-(diphenylalkyl)piperazine derivatives arereported to have affinities for sigma receptors (WO91/09594). However,this report mainly relates to the compounds which have no substituentsat a phenyl ring, and it does not recite studies about influence onaffinities for sigma receptors by introducing substituents into thephenyl ring.

The following prior arts disclose compounds whose chemical structuresare similar to those of the compounds of this invention, thoughdifferent from this invention in objects, actions and effects. Many1,4-(diphenylalkyl)piperazine derivatives having no substituents at bothof two phenyl rings and having substituents at both of two phenyl ringshave already been synthesized (Chem. Ber., 100, 3045 (1967); J. Pharm.Sci., 72, 304 (1983)). However, there are few reports of research about1,4-(diphenylalkyl)piperazine derivatives having substituents at onlyone phenyl ring and having no substituents at the other phenyl ring.

For example, only a compound wherein the 3rd-position of the phenyl ringis substituted by methoxy group and the 2nd-position is substituted byhydroxyl group (Pharmazie, 29, 189 (1970)) and a compound wherein the2nd-, 3rd- and 4th-positions of one phenyl ring are substituted bymethoxy groups (Japanese Patent Laid-open Publication No. 55-83771) arereported as compounds wherein one phenyl ring has no substituents andthe other phenyl ring has alkoxy groups. Of course, affinities for sigmareceptors have not been reported about these compounds.

It has not been studied yet how affinities for sigma receptors vary byintroducing substituents into the phenyl ring of1,4-(diphenylalkyl)piperazine derivatives, and it was an importantsubject to find a compound having a high affinity for sigma receptors byintroducing substituents into the phenyl ring.

In addition, it has not been studied fully to introduce at least onesubstituent into only one phenyl ring of 1,4-(diphenylalkyl)piperazinederivatives, and it was an interesting subject to synthesize and studysuch compounds.

The inventors synthesized novel 1,4-(diphenylalkyl)piperazinederivatives having specific substituents at only one phenyl ring andexamined effects of the compounds on sigma receptors. As the result ofthe examination, compounds having two alkoxy groups at only one phenylring were found to have high affinities for sigma receptors.

Furthermore it was found that these compounds have not only highaffinities for sigma receptors but also improving effects on learningdisorder due to cerebrovascular disorder and increasing effects on theamount of intracerebral acetylcholine, and that the compounds areparticularly useful for therapeutic agents for cerebral neural functiondisorders.

SUMMARY OF THE INVENTION

This invention relates to the compounds represented by following formulaI!, salts thereof (hereinafter referred to as "the compounds of thisinvention") and therapeutic agents for cerebral neural functiondisorders which comprise them as active ingredients: ##STR2## wherein,R¹ and R² are the same or different and each represents a lower alkoxygroup; "A" and "B" are the same or different and each represents a loweralkylene group.

The same definition is applied hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

The terms defined above are explained as follows in more detail;

The term "lower alkoxy" stands for straight or branched alkoxy having 1to 6 carbon atoms exemplified by methoxy, ethoxy, propoxy, isopropoxy,t-butoxy and hexyloxy.

The term "lower alkylene" stands for straight or branched alkylenehaving 1 to 6 carbon atoms exemplified by methylene, ethylene,propylene, butylene, (dimethyl)methylene and (diethyl)methylene.

The salts of the compound of this invention are pharmaceuticallyacceptable salts such as hydrochloride, sulfate, maleate and fumarate.

Preferred examples of the groups defined above are explained as followsin detail.

Preferred examples of the lower alkylene groups "A" and "B" are straightalkylene group(s) having 2 to 4 carbon atoms, that is, ethylene,propylene and/or butylene. Preferred examples of the combination of "A"and "B" are shown below;

"A" is propylene and "B" is ethylene,

both "A" and "B" are propylene,

both "A" and "B" are ethylene,

"A" is butylene and "B" is ethylene.

Particularly preferred examples of the combination of "A" and "B" areshown below;

"A" is propylene and "B" is ethylene,

both "A" and "B" are propylene.

Each of R¹ and R² is preferably a methoxy group. In particular, acompound wherein methoxy groups substitute at vicinal positions in onephenyl ring is preferable. The most preferred example is a compoundwherein methoxy groups substitute at the 3rd- and 4th-positionsrespectively.

Preferred examples of practical compounds are 1-2-(3,4-dimethoxyphenyl)ethyl!-4-(3-phenylpropyl)piperazine, 1-2-(3,4-dimethoxyphenyl)ethyl!-4-(2-phenylethyl)piperazine, 1-2-(3,4-dimethoxyphenyl)ethyl!-4-(4-phenylbutyl)piperazine, 1-3-(3,4-dimethoxyphenyl)propyl!-4-(3-phenylpropyl)piperazine, or saltsthereof.

Particularly preferred examples of compounds are 1-2-(3,4-dimethoxyphenyl)ethyl!-4-(3-phenylpropyl)piperazine, 1-3-(3,4-dimethoxyphenyl)propyl!-4-(3-phenylpropyl)piperazine, or saltsthereof.

Typical synthetic methods for preparing the compounds of this inventionare shown in the following reaction schemes 1) and 2). ##STR3## whereinX is halogen or a reactive group exemplified by a loweralkanesulfonyloxy group. The same definition applies to the reactionbelow.

In this method, the compound of the formula V! is prepared by reactingthe compound of the formula IV! with 2-bromoethanol. The compound of theformula V! is reacted with thionyl chloride, methanesulfonyl chloride,etc. to give the compound of the formula VI!, which is then reacted withthe amine derivative of the formula VII! to give the compound of thisinvention represented by the formula I!. ##STR4##

In this method, the reaction order of method 1) is reversed, andreaction conditions, etc. are the same as those of method 1).

The compounds prepared by the above methods can be converted into theirsalts as previously mentioned by conventional method.

Some of the compounds of the formula I! have optical isomers, and theseisomers are also included in this invention.

In order to study the utility of the compounds of this invention, anexperiment was performed to examine affinities of the compounds forsigma receptors. Details are shown in the article of PharmacologicalTest described later in this specification. The inventors examinedaffinities of the compounds for sigma receptors using ³ H!(+)-SKF-10047or ³ H!(+)-PTZ as labeled ligands. As the result of the examination, thecompounds of this invention were found to exhibit high affinities forsigma receptors.

Since compounds increasing the amount of intracerebral acetylcholine arereported to be useful for therapeutic agents for dementia, etc. (The NewEngland Journal of Medicine, 315, 1241-1245 (1986)), the amount ofacetylcholine in rat brain was then measured according to the report ofMatsuno et al. (Brain Research, 575, 315-319 (1992)). As the result ofthe measurement, the compounds of this invention were found to exhibitincreasing effects on the amount of acetylcholine.

In addition, an experiment was performed using learning disorder modelscaused by ischemia known as disease models of dementia caused bycerebrovascular disorder, that is, rats in transient ischemic conditionby blockading artery according to the method of Pulsinelli et al.(Stroke, 10, 267 (1979)). Evaluating the result of the experimentaccording to the method of Yasumatsu et al, (Folia PharmacologicaJaponica, 90, 321 (1987)), the compounds of this invention were found tohave improving effects on learning disorders.

From the results of the above pharmacological tests, it was found thatthe compounds of this invention have high affinities for sigma receptorsand that the compounds have wide pharmaceutical uses for therapeuticagents for diseases in which sigma receptors are concerned, for example,cerebral neural function disorders such as dementia, depression,schizophrenia and anxiety neurosis, diseases accompanying abnormalimmune response and cryptorrhea, digestive ulcer, etc. It was also foundthat the compounds have increasing effects on the amount ofintracerebral acetylcholine and improving effects on learning disordersdue to cerebrovascular disorder. From these findings, the compounds wereproved to be particularly useful for therapeutic agents for cerebralneural function disorders.

By the way, certain piperazine derivatives are reported to have amorphine-like physical dependence (Examined Japanese Patent PublicationNo. 61-33827). Such effect is not favorable for medicaments.Accordingly, an experiment was performed to examine whether thecompounds of this invention exhibit morphine-like effects. A compoundhaving the morphine-like effect is known to have a high affinity for μreceptors, and if the affinity for μ receptors is low, the morphine-likeeffect of the compound is judged to be also low. Affinities of thecompounds of this invention for μ receptors were examined using ³H!DAMGO as a labeled ligand. As the result of the examination, it wasfound that affinities of the compounds of this invention for μ receptorsare low and that the compounds substantially exhibit no morphine-likeeffects.

In order to apply one compound to a medicament, it is preferable thatthe difference between the amount for exhibiting effect and the amountfor exhibiting side-effect is large. That is to say, it is preferablethat the affinity for sigma receptors is high and the affinity for μreceptors is low in this invention, and the experimental resultsdescribed later demonstrate that the compounds of this invention areexcellent as medicaments.

The compounds of this invention can be administered orally orparenterally. Examples of dosage forms are tablet, capsule, softcapsule, granule, injection, etc. The preparations can be formulated bythe conventional methods. For example, oral preparations such as atablet, a capsule, a soft capsule and granule can be produced, ifnecessary, by adding diluents such as lactose, starch, crystallinecellulose or vegetable oil; lubricants such as magnesium stearate ortalc; binders such as hydroxypropylcellulose or polyvinyl pyrrolidone; adisintegrator such as calcium carboxymethylcellulose; coating agentssuch as hydroxypropylmethylcellulose, macrogol or silicone resin; or afilm forming agent such as gelatin coat. The dosage is adjusteddepending on symptoms, dosage form, etc., but the usual daily dosage is1 to 1000 mg, which can be given in one or a few divided doses.

THE BEST EMBODIMENT OF THE INVENTION Reference Examples (Preparation ofIntermediates) Reference Example 1

N,N-Bis(2-hydroxyethyl)-2-(3,4-dimethoxyphenyl)ethylamine (referencecompound No. 1-1) ##STR5##

To a solution of 2-(3,4-dimethoxyphenyl)ethylamine (20 g) and2-bromoethanol (73.4 g) in ethanol (250 ml) was added potassiumcarbonate (50.2 g). The mixture was refluxed for 24 hours. The insolublematter was filtered out, the filtrate was concentrated in vacuo, andchloroform (300 ml) was added to the concentrate. This solution waswashed with a 10% aqueous solution of sodium bicarbonate and a saturatedsodium chloride solution, dried over anhydrous sodium sulfate, andconcentrated in vacuo. The oily residue was purified by silica gelcolumn chromatography to give 13.5 g (46%) of the titled compound.

IR (film, cm⁻¹) 3383, 2941, 1516, 1464, 1262, 1236, 1142, 1029

The following compound was prepared in the similar manner to ReferenceExample 1.

N,N-Bis(2-hydroxyethyl)-3-(3,4-dimethoxyphenyl)propylamine (referencecompound No. 1-2)

IR (film, cm⁻¹) 3386, 2941, 1515, 1463, 1261, 1156, 1029, 764

Reference Example 2

N,N-Bis(2-chloroethyl)-2-(3,4-dimethoxyphenyl)ethylamine hydrochloride(reference compound No. 2-1) ##STR6##

To a solution ofN,N-bis(2-hydroxyethyl)-2-(3,4-dimethoxyphenyl)ethylamine (referencecompound No. 1-1, 10.9 g) in chloroform (50 ml) was added thionylchloride (14.4 g) dropwise under ice-cooling. The mixture was refluxedfor 45 minutes. The reaction mixture was concentrated in vacuo, andisopropanol was added to the concentrate to give 10.2 g (74%) of thetitled compound.

mp 147°-149° C.

IR (KBr, cm⁻¹) 2326, 1520, 1466, 1268, 1238, 1159, 1140, 1028

The following compound was prepared in the similar manner to ReferenceExample 2.

N,N-Bis(2-chloroethyl)-3-(3,4-dimethoxyphenyl)propylamine hydrochloride(reference compound No. 2-2)

mp 112°-123° C. (ethyl acetate-isopropyl ether)

IR (KBr, cm⁻¹) 2394, 1519, 1471, 1263, 1234, 1157, 1138, 1025

Reference Example 3

N,N-Bis(2-hydroxyethyl)-2-phenylethylamine (reference compound No. 3-1)##STR7##

To a solution of 2-phenylethylbromide (20 g) in ethanol (100 ml) wereadded N,N-bis(2-hydroxyethyl)amine (90.8 g) and sodium iodide (21.6 g).The mixture was refluxed for 3 hours. The reaction mixture wasconcentrated in vacuo, saturated aqueous solution of sodium bicarbonatewas added to the concentrate, and the whole was extracted withchloroform. The organic layer was washed with a saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, andconcentrated in vacuo to give 17.5 g (77%) of the titled compound.

IR (film, cm⁻¹) 3382, 3026, 2947, 1495, 1455, 1047, 747, 700

The following compounds were prepared in the similar manner to ReferenceExample 3.

N,N-Bis(2-hydroxyethyl)-3-phenylpropylamine (reference compound No. 3-2)

IR (film, cm⁻¹) 3373, 2943, 1496, 1454, 1031, 749, 700

N,N-Bis(2-hydroxyethyl)-4-phenylbutylamine (reference compound No. 3-3)

IR (film, cm⁻¹) 3377, 2936, 1496, 1454, 1041, 748, 700

N,N-Bis(2-hydroxyethyl)-5-phenylpentylamine (reference compound No. 3-4)

IR (film, cm⁻¹) 3378, 2934, 1495, 1453, 1043, 747, 699

Reference Example 4

N,N-Bis(2-chloroethyl)-2-phenylethylamine hydrochloride (referencecompound No. 4-1) ##STR8##

To a solution of N,N-bis(2-hydroxyethyl)-2-phenylethylamine (referencecompound No. 3-1, 33.5 g) in chloroform (160 ml) was added thionylchloride (57.1 g) dropwise under ice-cooling while stirring. The mixturewas stirred at room temperature for 10 minutes, and refluxed for 1 hour.The reaction mixture was concentrated in vacuo, ethyl acetate andisopropyl ether were added to the concentrate, and the obtained crystalswere collected by filtration to give 39.2 g (87%) of the titledcompound.

mp 116°-117° C. (ethyl acetate-isopropyl ether)

IR (KBr, cm⁻¹) 3008, 2423, 1498, 1479, 1456, 766, 746, 704

The following compounds were prepared in the similar manner to ReferenceExample 4.

N,N-Bis(2-chloroethyl)-3-phenylpropylamine hydrochloride (referencecompound No. 4-2)

mp 98°-100 ° C. (ethyl acetate-isopropyl ether)

IR (KBr, cm⁻¹) 2965, 2360, 1484, 1458, 1325, 936, 753, 696

N,N-Bis(2-chloroethyl)-4-phenylbutylamine hydrochloride (referencecompound No. 4-3)

mp 100°-112° C. (ethyl acetate-isopropyl ether)

IR (KBr, cm⁻¹) 2945, 2459, 1487, 1444, 1420, 926, 741, 698

N,N-Bis(2-chloroethyl)-5-phenylpentylamine hydrochloride (referencecompound No. 4-4)

mp 69°-75° C. (ethyl acetate-isopropyl ether)

IR (KBr, cm⁻¹) 2937, 2859, 2459, 1454, 901, 742, 695

EXAMPLES Example 1

1- 2-(3,4-Dimethoxyphenyl)ethyl!-4-(3-phenylpropyl)piperazinedihydrochloride (compound No. 1-1) ##STR9##

To a solution ofN,N-bis(2-chloroethyl)-2-(3,4-dimethoxyphenyl)ethylamine hydrochloride(reference compound No. 2-1, 0.69 g) and 3-phenylpropylamine (0.41 g) indimethylformamide (20 ml) were added potassium carbonate (0.83 g) andsodium iodide (0.90 g). The mixture was stirred at 70° C. for 2 hours.To the reaction mixture, water was added, and the whole was extractedwith ethyl acetate. The organic layer was washed with water and asaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated in vacuo. The oily residue was dissolved inethanol, 6N hydrochloric acid (2 ml) was added thereto, and the solutionwas concentrated in vacuo to give 0.68 g (77%) of the titled compound(compound No. 1-1).

mp 258°-260° C. (decomp.)

IR (KBr, cm⁻¹) 3977, 2355, 1518, 1265, 1140, 1028, 754, 704

The following compounds were prepared in the similar manner to Example 1

1- 2-(3,4-Dimethoxyphenyl)ethyl!-4-(2-phenylethyl)piperazinedihydrochloride (compound No. 1-2)

mp 268°-272° C. (decomp.)

IR (KBr, cm⁻¹) 3430, 2938, 2300, 1519, 1447, 1264, 1234, 1026

1- 2-(3,4-Dimethoxyphenyl)ethyl!-4-benzylpiperazine dihydrochloride(compound No. 1-3)

mp 250°-253° C. (decomp.)

IR (KBr, cm⁻¹) 2978, 2360, 1520, 1467, 1267, 1236, 1149, 1027

1- 2-(3,4-Dimethoxyphenyl)ethyl!-4-(4-phenylbutyl)piperazinedihydrochloride (compound No. 1-4)

mp over 280° C. (ethanol)

IR (KBr, cm⁻¹) 2361, 1522, 1469, 1445, 1264, 1162, 1027, 696

1- 3-(3,4-Dimethoxyphenyl)propyl!-4-(2-phenylethyl)piperazinedihydrochloride (compound No. 1-5)

mp 254° C. (decomp., ethanol)

IR (KBr, cm⁻¹) 2360, 1518, 1455, 1236, 1139, 1028, 754, 703

1- 3-(3,4-Dimethoxyphenyl)propyl!-4-(3-phenylpropyl)piperazinedihydrochloride (compound No. 1-6)

mp 254°-257° C. (decomp., methanol)

IR (KBr, cm⁻¹) 2984, 2394, 1515, 1452, 1258, 1235, 1155, 1029

1- 3-(3,4-Dimethoxyphenyl)propyl!-4-(4-phenylbutyl)piperazinedihydrochloride (compound No. 1-7)

mp 256°-259° C. (decomp., ethanol)

IR (KBr, cm⁻¹) 2377, 1514, 1451, 1258, 1234, 1156, 1029, 699

Example 2

1-(3,4-Dimethoxybenzyl)-4-(2-phenylethyl)piperazine dihydrochloride(compound No. 2-1) ##STR10##

N,N-Bis(2-chloroethyl)-2-phenylethylamine hydrochloride (referencecompound No. 4-1, 1.0 g), 3,4-dimethoxybenzylamine (1.2 g), potassiumcarbonate (1.5 g) and sodium iodide (1.1 g) were suspended indimethylformamide (35 ml). This suspension was stirred at 30°-38° C. for2.5 hours. To the reaction mixture, iced water was added, and the wholewas extracted with ethyl acetate. The organic layer was washed withwater and then with a saturated sodium chloride solution, dried overanhydrous sodium sulfate, and concentrated in vacuo. The oily residuewas purified by silica gel column chromatography, and dissolved inmethanol. To this methanol solution, conc. hydrochloric acid was added,and the precipitated crystals were collected by filtration to give 0.8 g(55%) of the titled compound.

mp ca. 280° C. (decomp.)

IR (KBr, cm⁻¹) 3447, 2980, 2335, 1590, 1520, 1449, 1265, 1245, 1159,1022, 949, 914, 760, 701, 650

The following compounds were prepared in the similar manner to Example 2

1-(3,4-Dimethoxybenzyl)-4-(3-phenylpropyl)piperazine dihydrochloride(compound No. 2-2)

mp 257°-260° C. (decomp., ethanol)

IR (KBr, cm⁻¹) 2362, 1523, 1453, 1276, 1166, 1020, 750, 699

1- 2-(2,5-Dimethoxyphenyl)ethyl!-4-(3-phenylpropyl)piperazinedihydrochloride (compound No. 2-3)

mp 240° C. (decomp., ethanol)

IR (KBr, cm⁻¹) 2990, 2391, 1501, 1467, 1227, 1044, 959, 699

1-(3,4-Dimethoxybenzyl)-4-(4-phenylbutyl)piperazine dihydrochloride(compound No. 2-4)

mp 255° C. (decomp., ethanol)

IR (KBr, cm⁻¹) 2945, 2338, 1519, 1445, 1267, 1164, 1023, 761

1- 2-(3,4-Dimethoxyphenyl)ethyl!-4-(5-phenylpentyl)piperazinedihydrochloride (compound No. 2-5)

mp 260°-268° C. (decomp., ethanol)

IR (KBr, cm⁻¹) 2932, 2338, 1521, 1453, 1263, 1162, 1144, 700

Formulation Examples

Examples of the formulations of the compounds I! according to thisinvention are shown below.

    ______________________________________                                        (Tablet)                                                                      compound of this invention                                                                          1         mg                                            lactose               120       mg                                            crystalline cellulose 38        mg                                            low substituted hydroxypropylcellulose                                                              5         mg                                            hydroxypropylcellulose-L                                                                            5         mg                                            magnesium stearate    1         mg                                            total                 170       mg                                            compound of this invention                                                                          5         mg                                            lactose               175       mg                                            crystalline cellulose 68        mg                                            low substituted hydroxypropylcellulose                                                              10        mg                                            hydroxypropylcellulose-L                                                                            10        mg                                            magnesium stearate    2         mg                                            total                 270       mg                                            (Soft Capsule)                                                                compound of this invention                                                                          50        mg                                            vegetable oil         150       mg                                            gelatin coat          140       mg                                            total                 340       mg                                            (Injection)                                                                   compound of this invention                                                                          100       mg                                            sodium chloride       0.9       g                                             sodium hydroxide      q.s.                                                    sterile purified water                                                                              q.s.                                                    total                 100       ml                                            ______________________________________                                    

EFFECT OF THE INVENTION Pharmacological Test

1. In order to study the utility of the compounds of this invention,experiments were performed to examine affinities for sigma receptors.

1-1. Experiment Using 3H!(+)-SKF-10047 as a Labeled Ligand

Affinities for sigma receptors were determined by the following methodaccording to the report of Matsuno et al. (European Journal ofPharmacology, 231, 451-457 (1993)). (Experimental Method)

A membrane preparation was prepared by the following method according tothe paper of Tam et al. (Proc. Natl. Acad. Sci. USA, 80, 6703-6707(1983)).

A brain of a Hartley guinea pig (weight: 300-400 g) was excised, thebrain was homogenized in Tris-hydrochloric acid buffer (50 mM, pH 7.7,containing 0.32M sucrose) having a weight eight times that of the brain,and the homogenate was centrifuged to obtain a supernatant. Thesupernatant was ultracentrifuged for 20 minutes, the resulting pelletwas suspended in Tris-hydrochloric acid buffer (50 mM, pH 7.7, the samebuffer was used hereinafter), and the suspension was centrifuged againto obtain a membrane preparation.

The specific binding of ³ H!(+)-SKF-10047 was determined by thefollowing method in advance. To the membrane preparation suspended inTris-hydrochloric acid buffer was added ³ H!(+)-SKF-10047 (5 nM)dissolved in Tris-hydrochloric acid buffer without adding a testcompound, and they were allowed to react at 25° C. for 30 minutes.Completing the reaction, the reaction mixture was filtered with suctionthrough a glass filter, and radioactivity on the filter was measuredwith a liquid scintillation counter to determine total binding. Inaddition, to the membrane preparation was added a mixture of ³H!(+)-SKF-10047 (5 nM) and (+)-SKF-10047 (100 μM) having noradioactivity without adding the test compound, and the binding with themembrane preparation was determined in the same manner as describedabove. The obtained binding was defined as the non-specific binding. Thedifference between the total binding and the non-specific bindingobtained in this manner was defined as the specific binding.

Secondly, the binding of the membrane preparation and ³ H!(+)-SKF-10047was measured in the presence of the test compound while varying theconcentration of the test compound to determine the concentration of thetest compound in which the specific binding of ³ H!(+)-SKF-10047determined previously is inhibited by 50%, i.e., IC₅₀.

(Result)

Results with compounds No. 1-1, 1-2 and 1-3 are shown in Table 1 asexamples of the experimental results.

                  TABLE 1                                                         ______________________________________                                                       IC.sub.50 (nM)                                                 ______________________________________                                        compound No. 1-1 0.34                                                         compound No. 1-2 9.32                                                         compound No. 1-3 4.28                                                         ______________________________________                                    

As shown in Table 1, the compounds of this invention were recognized toinhibit the specific binding of ³ H!(+)-SKF-10047 remarkably in the lowconcentration, and the compounds were found out to have high affinitiesfor sigma receptors.

1-2. Experiment Using ³ H!(+)-PTZ as a Labeled Ligand

Affinities for sigma receptors were determined by the following methodusing ³ H!(+)-PTZ as a labeled ligand according to the report ofDeHaven-Hudkins et al. (Eur. I. Pharmacol,, 227, 371-378 (1992)).

(Experimental Method)

A membrane preparation was prepared by the following method according tothe paper of Tam et al. (Proc. Natl. Acad. Sci., USA, 80, 6703-6707(1983)).

A brain of a Hartley guinea pig (weight: 300-400 g) was excised, thebrain was homogenized in Tris-hydrochloric acid buffer (50 mM, pH 7.7,containing 0.32M sucrose) having a weight eight times that of the brain,and the homogenate was centrifuged to obtain a supernatant. Thesupernatant was ultracentrifuged for 20 minutes, the resulting pelletwas suspended in Tris-hydrochloric acid buffer (50 mM, pH 7.7, the samebuffer was used hereinafter), and the suspension was centrifuged againto obtain a membrane preparation.

The specific binding of ³ H!(+)-PTZ was determined by the followingmethod in advance. To the membrane preparation suspended inTris-hydrochloric acid buffer was added ³ H!(+)-PTZ (5 nM) dissolved inTris-hydrochloric acid buffer without adding a test compound, and theywere allowed to react at 37° C. for 150 minutes. Completing thereaction, the reaction mixture was filtered with suction through a glassfilter, and radioactivity on the filter was measured with a liquidscintillation counter to determine total binding. In addition, to themembrane preparation was added a mixture of ³ H!(+)-PTZ (5 nM) and(+)-PTZ (100 μM) having no radioactivity without adding the testcompound, and the binding with the membrane preparation was determinedin the same manner as described above. The obtained binding was definedas the non-specific binding. The difference between the total bindingand the non-specific binding obtained in this manner was defined as thespecific binding.

Secondly, the binding of the membrane preparation and ³ H!(+)-PTZ wasmeasured in the presence of the test compound while varying theconcentration of the test compound to determine the concentration of thetest compound in which the specific binding of ³ H!(+)-PTZ determinedpreviously is inhibited by 50%, i.e., IC₅₀.

(Result)

Results with compounds No. 1-1, 1-2, 1-4 and 1-6 are shown in Table 2 asexamples of the experimental results. The results are expressed inaverages of 4-11 samples.

                  TABLE 2                                                         ______________________________________                                                       IC.sub.50 (nM)                                                 ______________________________________                                        compound No. 1-1 33.1                                                         compound No. 1-2 18.0                                                         compound No. 1-4 10.7                                                         compound No. 1-6 14.9                                                         ______________________________________                                    

As shown in Table 2, the compounds of this invention were recognized toinhibit the specific binding of ³ H!(+)-PTZ remarkably in the lowconcentration and to have high affinities for sigma receptors, as wellas in examining ³ H!(+)-SKF-10047 as a labeled ligand.

2. Experiment on the Increasing Effects on the Amount of IntracerebralAcetylcholine

Since compounds increasing the amount of intracerebral acetylcholinewere reported to be useful for therapeutic agents for dementia, etc.(The New England Journal of Medicine, 315, 1241-1245 (1986)), anexperiment was performed to examine effects of the compounds of thisinvention on the amount of acetylcholine in rat brain.

(Experimental Method)

The amount of acetylcholine in rat brain was measured by the followingmethod using intracerebral microdialysis method according to the reportof Matsuno et al. (Brain Research, 575, 315-319 (1992)).

A probe was inserted in a brain of a male Wistar rat (weight: 280-300g), Ringer's solution containing 3 μM eserine sulfate was perfused inthe brain, acetylcholine recovered from the probe was determined byhigh-speed liquid chromatography. The amount of acetylcholine in ratbrain was measured with time. When it became constant, the test compoundsuspended in 1% methylcellulose solution was administered orally to therat, and the amount of intracerebral acetylcholine was measured. Theamount of acetylcholine in rat brain (average of six samples) to whichthe test compound was not administered was used as a control. Table 3shows the results expressed in percentages of amount of acetylcholine(averages of 3-7 samples in 30 minutes after administration of the testcompound) to the control.

(Results)

                  TABLE 3                                                         ______________________________________                                                      amount of                                                                              amount of                                                            administration                                                                         acetylcholine                                                        (mg/kg)  (% control)                                            ______________________________________                                        compound No. 1-1                                                                              10         154.3                                                              20         170.0                                              compound No. 1-4                                                                              40         146.2                                                              80         164.9                                              compound No. 1-6                                                                              20         146.1                                                              40         176.9                                              ______________________________________                                    

As shown in Table 3, the compounds of this invention were recognized tohave excellent effects to increase the amount of intracerebralacetylcholine.

3. Experiment on Affinities for μ Receptors

Affinities for μ receptors were determined by the following methodaccording to the report of Nabeshima et al. (Eur. J. Pharmacol., 114,197-207 (1985)). As a ³ H!-labeled ligand of μ receptors, ³ H!DAMGOwhose high selectivity of μ receptors had been reported was used (Br. J.Pharmac., 77, 461-469, (1982)).

(Experimental Method)

A membrane preparation was prepared by the following method according tothe report of Kosterlitz et al. (Br. J. Pharmac., 68, 333-342 (1980)).

A brain of a male Wistar rat (weight: ca. 300 g) was excised, the brainwas homogenized in Tris-hydrochloric acid buffer (50 mM, pH 7.7, thesame buffer was used hereinafter) having a weight 20 times that of thebrain, and the homogenate was ultracentrifuged for 15 minutes to obtaina pellet. This pellet was suspended in Tris-hydrochloric acid buffer,the suspension was incubated at 37° C. for 30 minutes, ultracentrifugedfor 15 minutes, and the resulting pellet was used as a membranepreparation.

The specific binding of ³ H!DAMGO was determined by the following methodin advance. To the membrane preparation suspended in Tris-hydrochloricacid buffer was added ³ H!DAMGO (1 nM) dissolved in Tris-hydrochloricacid buffer without adding a test compound, and they were allowed toreact at 25° C. for 30 minutes. Completing the reaction, the reactionmixture was filtered with suction through a glass filter, andradioactivity on the filter was measured with a liquid scintillationcounter to determine total binding. In addition, to the membranepreparation was added a mixture of ³ H!DAMGO (1 nM) and naloxone (5 μM)without adding the test compound, and the binding with the membranepreparation was determined in the same manner as described above. Thebinding was defined as the non-specific binding. The difference betweenthe total binding and the non-specific binding obtained in this mannerwas defined as the specific binding.

Secondly, the binding of the membrane preparation and ³ H!DAMGO wasmeasured in the presence of the test compound while varying theconcentration of the test compound to determine the concentration of thetest compound in which the specific binding of ³ H!DAMGO determinedpreviously is inhibited by 50%, i.e., IC₅₀.

(Result)

Examples of the experimental results are shown below. Compounds No. 1-1,1-2 and 1-3 exhibit IC₅₀ of higher than 10,000 nM, and the compounds ofthis invention were hardly recognized to inhibit the specific binding of³ H!DAMGO. From these results, it turned out that affinities of thecompounds of this invention for μ receptors are very low and that thecompounds hardly exhibit morphine-like effects.

As apparent from the results of the above pharmacological tests, thecompounds of this invention have high affinities for sigma receptors,hardly exhibit morphine-like effects, and have wide pharmaceutical usesfor therapeutic agents for diseases in which sigma receptors areconcerned, for example, cerebral neural function disorders such asdementia, depression, schizophrenia and anxiety neurosis, diseasesaccompanying abnormal immune response and cryptorrhea, digestive ulcer,etc. In addition, the compounds of this invention are particularlyuseful for therapeutic agents for cerebral neural function disorderscoupled with increasing effects on the amount of intracerebralacetylcholine and improving effects on learning disorders caused by acerebrovascular disorder.

INDUSTRIAL POSSIBILITY OF UTILIZATION

The compounds of this invention, that is, 1,4-(diphenylalkyl)piperazinederivatives have affinities for sigma receptors and are useful fortherapeutic agents for cerebral neural function disorders such asdementia, depression, schizophrenia and anxiety neurosis, diseasesaccompanying abnormal immune response and cryptorrhea, digestive ulcer,etc.

What is claimed is:
 1. A compound represented by the formula I! or asalt thereof, ##STR11## wherein R¹ and R² are the same or different andeach represents a lower alkoxy group; A and B are the same or differentand each represents a C₂ -C₄ alkylene group.
 2. The compound or a saltthereof as defined in claim 1 wherein A is --(CH₂)₂ --, --(CH₂)₃ -- or--(CH₂)₄ --.
 3. The compound or a salt thereof as defined in claim 1wherein B is --(CH₂)₂ -- or --(CH₂)₃ --.
 4. The compound or a saltthereof as defined in claim 1 wherein A is --(CH₂)₃ -- and B is --(CH₂)₂--.
 5. The compound or a salt thereof as defined in claim 1 wherein eachof A and B is --(CH₂)₃ --.
 6. The compound or a salt thereof as definedin claim 1 wherein each of A and B is --(CH₂)₂ --.
 7. The compound or asalt thereof as defined in claim 1 wherein A is --(CH₂)₄ -- and B is--(CH₂)₂ --.
 8. The compound or a salt thereof as defined in claim 1wherein each of R¹ and R² is a methoxy group.
 9. The compound or a saltthereof as defined in claim 1 wherein R¹ and R² are both methoxy groupsand the compound is of the following formula: ##STR12##
 10. A compoundrepresented by the formula II! or a salt thereof ##STR13##
 11. Acompound represented by the formula III! or a salt thereof ##STR14## 12.A therapeutic agent for treating a cerebral neural function disorderwhich comprises (a) a compound of the following formula or a saltthereof as an active ingredient: ##STR15## wherein R¹ and R² are thesame or different and each represents a lower alkoxy group; A and B arethe same or different and each represents a C₂ -C₄ alkylene group, and(b) a diluent, lubricant, disintegrator, binder, coating agent or filmforming agent.
 13. The therapeutic agent for treating a cerebral neuralfunction disorder as defined in claim 12 wherein A is --(CH₂ (₂ --,--(CH₂)₃ -- or --(CH₂)₄ --.
 14. The therapeutic agent for treating acerebral neural function disorder as defined in claim 12 wherein B is--(CH₂)₂ -- or --(CH₂)₃ --.
 15. The therapeutic agent for treating acerebral neural function disorder as defined in claim 12 wherein A is--(CH₂)₃ -- and B is --(CH₂)₂ --.
 16. The therapeutic agent for treatinga cerebral neural function disorder as defined in claim 12 wherein eachof A and B is --(CH₂)₃ --.
 17. The therapeutic agent for treating acerebral neural function disorder as defined in claim 12 wherein each ofA and B is --(CH₂)₂ --.
 18. The therapeutic agent for treating acerebral neural function disorder as defined in claim 12 wherein A is--(CH₂)₄ -- and B is --(CH₂)₂ --.
 19. The therapeutic agent for treatinga cerebral neural function disorder as defined in claim 12 wherein eachof R¹ and R² is a methoxy group.
 20. The therapeutic agent for treatinga cerebral neural function disorder as defined in claim 12 wherein R¹and R² are both methoxy groups and the compound is of the followingformula: ##STR16##
 21. The therapeutic agent for treating a cerebralneural function disorder as defined in claim 12, wherein the compound isof the following formula: ##STR17##
 22. The therapeutic agent fortreating a cerebral function disorder as defined in claim 12, whereinthe compound is of the following formula: ##STR18##